Corticotropin-Releasing Factor (hereinafter abbreviated as “CRF”) is a neuropeptide consisting of 41 amino acids which was first isolated from ovine hypothalamus [Science, 213, 1394 (1981)], after which its presence was also confirmed in rat [Proc. Natl. Acad. Sci. USA, 80, 4851 (1983)] and in human [EMBO J. 5, 775 (1983)]. CRF is most abundant in the pituitary gland and hypothalamus, and is also widely distributed throughout cerebral cortex, cerebellum and other areas of the brain. Its presence has also been confirmed in peripheral tissue such as the placenta, adrenal gland, lung, liver, pancreas and gastrointestinal tract [Exp. Clin. Endocrinol. Diabetes, 105, 65 (1997)]. Two subtype CRF receptor has been described, CRF1 and CRF2, and CRF1 receptor is reported to be widely distributed in cerebral cortex, cerebellum, olfactory bulb, pituitary gland, amygdaloidal nucleus and elsewhere. Recently, 2 subtypes of the CRF2 receptor have been confirmed, CRF2α and CRF2β, of which it has been discovered that CRF2α receptors are abundantly distributed in the hypothalamus, septal nucleus and choroid plexus, while CRF2β receptors are primarily distributed in peripheral tissue such as the skeletal muscle, or in the cerebral blood vessels of the central nervous system [Exp. Clin. Endocrinol. Diabetes, 105, 65 (1997)]. The fact that each of these receptors has a different distribution profile suggests that their roles are also different. CRF is produced and secreted in the hypothalamus and promotes stress-induced release of adrenocorticotropic hormone (ACTH) [Recent Prog. Horm. Res., 39, 245 (1983)]. In addition to its endocrine role, CRF also functions as a neurotransmitter or neuromodulator in the brain, integrating electrophysiological, autonomic and behavioral changes in response to stress [Brain Res. Rev., 15, 71 (1990); Pharmacol. Rev., 43, 425 (1991)].
CRF has been implicated in a variety of disease to date, as indicated by the following publications.
It was reported that elevated concentrations of CRF in the cerebrospinal fluid of patients with major depression compared with healthy individuals; CRF-mRNA levels in the hypothalamus of depressive patients are higher than that of healthy individuals; CRF receptors in cerebral cortex are reduced in suicide victims; plasma ACTH increase is diminished with administration of CRF to depressive patients [Journal of Endocrinology, 160, 1 (1999)]; CRF levels in the cerebrospinal fluid of some anxiety patients with obsessive-compulsive disorder, posttraumatic stress disorder or Tourette's syndrome are higher than in that of healthy individuals [Journal of Endocrinology, 160, 1 (1999)]; plasma ACTH increase is diminished with administration of CRF to panic disorder patients [Exp. Clin. Endcrinol. Diabetes, 105, 65 (1997)]; anxiety behavior has been observed in experimental animals by intracerebral administration of CRF. In addition, anxiety behavior is observed more frequently in CRF overexpressing mice than in normal mice [Journal of Endocrinology, 160, 1 (1999)], and CRF levels in the locus coeruleus are reduced by administration of anxiolytics [Exp. Clin. Endcrinol. Diabetes, 105, 65 (1997)]. Also, α-helical CRF(9-41), a peptide CRF antagonist, exhibits an antianxiety action in animal models [Brain Res., 509, 80 (1990); Regulatory Peptides, 18, 37 (1987); J. Neurosci., 14(5), 2579 (1994)]; and abnormal behavior withdrawal from alcohol or addictive drugs such as cocaine are inhibited by α-helical CRF(9-41), a peptide CRF antagonist [Psychopharmacology, 103, 227 (1991)].
CRF inhibits sexual behavior in rat [Nature, 305, 232 (1983)]; CRF reduces sleep in rat and is thus implicated the involvement in sleep disorder [Pharmacol. Biochem. Behav., 26, 699 (1987)]; α-helical CRF(9-41), a peptide CRF antagonist, suppresses brain damage or electroencephalogram disturbances due to brain ischemia or NMDA receptor activation [TIPS, 17, 166 (1996)]; CRF elicits electroencephalogram and induces convulsions [Brain Res., 278, 332 (1983)]; cerebrospinal CRF levels are elevated in schizophrenic patients compared with healthy individuals [Am. J. Psychiatry, 144(7), 873 (1987)]; CRF content in cerebral cortex is reduced in Alzheimer's disease patients, Parkinson's disease patients and progressive supranuclear palsy patients [Neurology, 37, 905 (1987)]; and CRF is reduced in the ganglia in Huntington's disease [Neurology, 37, 905 (1987); Brain Res., 437, 355 (1987)]. In addition, CRF administration has been found to enhance learning and memory in rat [Exp. Clin. Endcrinol. Diabetes, 105, 65 (1997)].
CRF content in cerebrospinal fluid are reduced in amyotrophic lateral sclerosis patients. Oversecretion of ACTH and adrenocorticosteroids are exhibited in mice overexpressing CRF, these mice display abnormalities similar to Cushing's syndrome, including muscular atrophy, alopecia and infertility [Endocrinology, 130(6), 3378 (1992)]; cerebrospinal CRF is elevated in anorexia nervosa patients compared with healthy individuals, and plasma ACTH increase is low with administration of CRF to anorexia nervosa patients; and CRF suppress feeding in experimental animals [TIPS, 17, 166 (1996)]. Moreover, α-helical CRF(9-41), a peptide CRF antagonist, improves stress-induced hypophagia in animal models [Brain Res. Bull., 17(3), 285 (1986)]; CRF has suppressed body weight gain in hereditary obese animals; a link has been suggested between low CRF levels and obesity syndrome; and the anorexic action and the body weight loss action of serotonin reuptake inhibitors has been possibly mediated by CRF release [TIPS, 17, 166 (1996)].
CRF acts centrally or peripherally to weaken gastric contraction and reduce gastric emptying [Annals of the New York Academy of Sciences, 697, 233 (1993)]. Furthermore, reduced gastric function induced by abdominal surgery is recovered by α-helical CRF(9-41), a peptide CRF antagonist [Am. J. Physiol., 262, G616 (1992)]; and CRF promotes secretion of bicarbonate ion in the stomach, thereby lowering gastric acid secretion and suppressing cold restraint stress ulcers [Am. J. Physiol., 258, G152 (1990)]. Also, administration of CRF increases ulcers in non-restraint stress animals [Life Sci., 45, 907 (1989)]; and CRF suppresses small intestinal transit and promotes large intestinal transit, and defecation is induced. In addition, α-helical CRF(9-41), a peptide CRF antagonist, has a inhibiting action against restraint stress-induced gastric acid secretion, reduced gastric emptying, reduced small intestinal transit and promoted large intestinal transit [Gastroenterology, 95, 1510 (1988)]; psychological stress in healthy individuals increases anxiety or sensations of gas and abdominal pain during colonic distension and CRF lowers the discomfort threshold [Gastroenterol., 109, 1772 (1995); Neurogastroenterol. Mot., 8, 9 (1996)]; and irritable bowel syndrome patients experience excessive acceleration of colonic motility with CRF administration compared to healthy individuals [Gut, 42, 845 (1998)].
Administration of CRF increases blood pressure, heart rate and body temperature, while α-helical CRF(9-41), a peptide CRF antagonist, suppresses stress-induced increases in blood pressure, heart rate and body temperature [J. Physiol., 460, 221 (1993)]. CRF production is increased locally in inflammation sites in experimental animals and in the synovial fluid of rheumatic arthritis patients [TIPS, 17, 166 (1996)]; CRF provokes degranulation of mast cells and promotes vascular permeability [Endocrinology, 139(1), 403 (1998)]; CRF is detected in autoimmune thyroiditis patients [Am. J. Pathol., 145, 1159 (1994)]; administration of CRF to experimental autoimmune encephalomyelitis rats has notably suppressed progression of symptoms such as paralysis [J. Immunol., 158, 5751 (1997)]; and urocortin (a CRF analogue) has increased growth hormone secretion in a pituitary adenoma culture system from an acromegalia patient [Endocri. J, 44, 627 (1997)]. Furthermore, CRF simulates secretion of cytokines such as interleukin-1 and interleukin-2 by leukocytes [J. Neuroimmunol., 23, 256 (1989); Neurosci. Lett., 120, 151 (1990)]; and CRF administration and stress both suppress T lymphocyte proliferation and natural killer cell activity. α-helical CRF(9-41), a peptide CRF antagonist, improves the reduced function of these immune cells caused by CRF administration or stress [Endocrinology, 128(3), 1329 (1991)], and breathing is notably increased by administration of CRF [Eur. J. Pharmacol., 182, 405 (1990)]. Finally, aggravated breathing and insomnia have been observed as a result of CRF administration to elderly patients under chronic artificial respiration [Acta Endocrinol. Copenh., 127, 200 (1992)].
The research cited above suggests that CRF antagonists may be expected to exhibit excellent effects for treatment or prevention of depression and depressive symptoms such as major depression, single-episode depression, recurrent depression, depression-induced child abuse and postpartum depression, mania, anxiety, generalized anxiety disorder, panic disorder, phobia, obsessive-compulsive disorder, posttraumatic stress disorder, Tourette's syndrome, autism, affective disorder, dysthymia, bipolar disorder, cyclothymic personality, schizophrenia, Alzheimer's disease, senile dementia of Alzheimer's type, neurodegenerative disease such as Parkinson's disease and Huntington's disease, multi-infarct dementia, senile dementia, anorexia nervosa, hyperphagia and other eating disorders, obesity, diabetes, alcohol dependence, pharmacophilia for drugs such as cocaine, heroin or benzodiazepines, drug or alcohol withdrawal symptoms, sleep disorder, insomnia, migraine, stress-induced headache, muscle contraction induced headache, ischemic neuronal damage, excitotoxic neuronal damage, stroke, progressive supranuclear palsy, amyotrophic lateral sclerosis, multiple sclerosis, muscular spasm, chronic fatigue syndrome, psychosocial dwarfism, epilepsy, head trauma, spinal cord injury, cheirospasm, spasmodic torticollis, cervicobrachial syndrome, primary glaucoma, Meniere's syndrome, autonomic imbalance, alopecia, neuroses such as cardiac neurosis, gastric neurosis and bladder neurosis, peptic ulcer, irritable bowel syndrome, ulcerative colitis, Crohn's disease, diarrhea, constipation, postoperative ileus, stress-associated gastrointestinal disorders and nervous vomiting, hypertension, cardiovascular disorders such as angina pectoris nervosa, tachycardia, congestive heart failure, hyperventilation syndrome, bronchial asthma, apneusis, sudden infant death syndrome, inflammatory disorders (e.g., rheumatic arthritis, osteoarthritis, lumbago, etc.), pain, allergosis (e.g., atopic dermatitis, eczema, hives, psoriasis, etc.), impotence (erectile dysfunction), menopausal disorder, fertilization disorder, infertility, cancer, HIV infection-related immune dysfunction, stress-induced immune dysfunction, hemorrhagic stress, Cushing's syndrome, thyroid function disorder, encephalomyelitis, acromegaly, incontinence, osteoporosis, and the like. As examples of CRF antagonists there have been reported peptide CRF receptor antagonists with modifications or deletions of portions of the amino acid sequence of human or other mammalian CRF, and such antagonists have shown ACTH release-inhibiting action or anxiolytic action [Science, 224, 889(1984); J. Pharmacol. Exp. Ther., 269, 564 (1994); Brain Res. Rev., 15, 71 (1990)]. However, peptide derivatives have low utility value as drugs from the standpoint of pharmacokinetics including their in vivo chemical stability, oral absorption, bioavailability and intracerebral transport.
The following nonpeptide CRF antagonists have been reported.    [1] Pyrazolotriazine compounds (WO0059907), pyrazolopyrimidine compounds (WO0059908), imidazo[1,2-a]pyrazine compounds (WO0206286, WO0262800) and imidazo[1,2-a]pyridine compounds (WO9835967, WO02062800); and    [2] Benzimidazole compounds (EP0812831), imidazopyrimidine compounds and imidazopyridine compounds (EP0994877), imidazo[4,5-c]pyrazole compounds (WO9910350), benzimidazole compounds, imidazo-pyridine compounds, imidazo-pyridazine compounds and imidazo-triazine compounds (WO0001697), 1H-imidazo[4,5-d]pyridazin-7-one compounds and 3H-imidazo[4,5-c]pyridin-4-one compounds (WO0039127), imidazopyrimidine compounds and imidazopyridine compounds (WO0144248) and imidazole compounds (WO02058704).
However, none of these are compounds having a substituted amino group bonded at the 3-position and a substituted phenyl group bonded at the 7-position of pyrazolo[1,5-a]pyridine, and no compounds are known which exhibit CRF antagonism and have pyrazolo[1,5-a]pyridine as the skeleton, with a substituted amino group bonded at the 3-position and a substituted phenyl group bonded at the 7-position.
The following compounds which have pyrazolo[1,5-a]pyridine structure have also been reported: U.S. Pat. No. 5,457,200, U.S. Pat. No. 4,925,849, U.S. Pat. No. 5,565,468 and U.S. Pat. No. 5,691,347.
However, none of the compounds described in these publications are mentioned as exhibiting CRF receptor antagonism, antidepressive action or antianxiety action. (For example, the compounds described in U.S. Pat. No. 5,457,200 are mentioned only in terms of their use for colorimetry. The compounds described in U.S. Pat. No. 4,925,849 are mentioned only in terms of their use as diuretics and treatment agents for hypertension. The compounds described in U.S. Pat. No. 5,565,468 are mentioned only in regard to their angiotensin II antagonism and vasoconstrictive action. The compounds described in U.S. Pat. No. 5,691,347 are described in terms of their use as treatment agents for atherosclerosis and hypercholestelemia.)
Furthermore, when the structures of the compounds described in each of these publications are compared, none of the compounds are compounds having a substituted amino group bonded at the 3-position and a substituted phenyl group bonded at the 7-position of pyrazolo[1,5-a]pyridine. In other words, no compounds are known which have a substituted amino group bonded at the 3-position and a substituted phenyl group bonded at the 7-position of pyrazolo[1,5-a]pyridine, as according to the present invention, and absolutely no method is known for synthesis of such compounds.